PROJECT SUMMARY/ABSTRACT Encephalitis is a heterogeneous syndrome defined by inflammation of the brain parenchyma leading to altered mental status and frequently, many other neurologic signs and symptoms including seizures, paralysis, hypoventilation and in some cases, death. Well over 100 viruses, autoantibodies, parasites, bacteria and fungi cause encephalitis, but in at least half of cases, no etiology is identified. Failure to identify an etiologic agent delays targeted therapies to patients and leads to empiric treatment trials that are sometimes ineffective and other times, actually exacerbate the patient's underlying condition. My goal in seeking a K08 Mentored Clinical Scientist Research Career Development Award is to acquire the necessary training, practical experience and knowledge to make major advances in our understanding of the causes of encephalitis. My long-term goal is to reduce the large number of idiopathic encephalitis cases by enhancing a novel diagnostic platform. I hypothesize that a novel molecular approach will improve the limits of detection for microbes in our next-generation sequencing (NGS) assay that aims to detect any class of microbe in cerebrospinal fluid and brain tissue (Subaim 1A). I hypothesize that a novel statistical approach will help to rigorously discriminate between microbial contamination vs. true infection in the metagenomic data collected from our NGS assay (Subaim 1B). I will harness these new molecular and analytic approaches to more frequently and accurately identify pathogens via metagenomic NGS in an ongoing, multicenter, prospective cohort study of patients with idiopathic encephalitis (Aim 2). During my self-designed fellowship in Neuro-Infectious Diseases at Massachusetts General Hospital and Boston University's National Emerging Infectious Diseases Laboratories, I acquired a unique skillset and was recruited back to UCSF as an Assistant Adjunct Professor in the Department of Neurology. I have put together a world-class team of mentors and advisors to guide me through this career development phase in order to launch myself successfully as an independent investigator. The research environment at UCSF is exceptional and includes cutting edge scientists and state-of-the-art equipment in the California Institute of Quantitative Biosciences (QB3) and the Sandler Neurosciences Building. My training plan is specifically designed to provide advanced training in clinical research methods, statistics, bioinformatics and microbiology that will be necessary to actualize these goals and position me to obtain R01 or equivalent funding as an independent investigator. I also intend to be an active participant in the K-Scholars program.